The deiodinases initiate or terminate thyroid hormone (TH) action. Studies pioneered in my laboratory unveiled that the activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease TH signaling in a tissue- and temporal-specific fashion. In other words, D2 and D3 determine the intensity of thyroid signaling independently of plasma T3 (the biologically active TH. Our studies revealed that these mechanisms can be modulated by a wide variety of signaling molecules such as the hedgehog family of proteins, bile acids, HIF-1, NF-B, and a number of xenobiotic substances. These studies have indicated that deiodinases play a broad role in the control of metabolism and disease state, the understanding of which is the focus of this application. In this proposal, we focus on the role of inactivating deiodinase (D3) in three different tissues, brain, heart and pancreas (specifically beta cells). Our publications and preliminary data show that D3 plays a crucial role in these three tissues. For example, in brain, we have shown that D3 translocates into the nucleus to inactivate thyroid hormone (T3) to reduce metabolism in neurons. In addition, we have demonstrated that D3 plays a critical role in myocardial fibrosis and cardiac remodeling using paternally imprinted D3 heterozygous mouse models. Finally, we have published that a D3 knockout mouse has impaired glucose tolerance and has a defect in insulin secretion from pancreatic beta cells. These discoveries underlie a role of D3-controlled termination of TH signaling in brain, heart and pancreatic beta cells with repercussions for metabolic regulation in brain, adrenergic or angiotensin signaling in heart and insulin secretion mechanism in pancreatic beta cells. Our studies indicate that these novel D3 mediated adaptive mechanisms are operating in settings of three different tissues, such as brain, heart and pancreas. This proposal investigates the D3 paradigm from the perspective of various physiological or pathological contexts in different tissues, examining the effects of inactivating thyroid hormone signaling by D3 in the model of stroke, cardiac hypertrophy and diabetes. The novel findings that (i) D3 plays an important protective role in neuronal hypoxia/ischemia, (ii) myocardial D3 affects adrenergic and angiotensin signaling for myocardiac fibrosis, and that (iii) D3 is crucial n pancreatic beta cell development, expansion and insulin secretion, form the basis of this proposal.